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K T Riabowol

Publications and source records attributed to K T Riabowol.

25 records · Page 2Linked to original sources
PubMedDate not supplied

Differential effects of transforming growth factor-beta 1 on the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in young and old human fibroblasts.

The balance between the activities of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) is an important control point in tissue remodeling. Previous studies have demonstrated elevated expression of the MMPs collagenase and stromelysin-1 by aged human diploid fibroblasts compared to early-passage cultures. We show here that aging cells display an altered response to transforming growth factor-beta 1 (TGF beta 1) that selectively affects MMP mRNA expression. In both young and old cells, phorbol myristoyl-13 acetate (PMA) induced the expression of transcripts of collagenase, stromelysin-1, gelatinase-B, TIMP-1, and TIMP-3. In young cells, TGF beta 1 reciprocally modulated PMA-induced MMP and TIMP gene expression leading to reduced levels of transcripts for the MMPs and augmented accumulation of TIMP-1 and TIMP-3 mRNAs. However, repressing effects of TGF beta 1 on collagenase, stromelysin-1, and gelatinase-B RNA expression were not apparent in old cells, though induction of the TIMP genes was unimpaired. By electrophoretic mobility shift analysis the nuclear transcription factors AP1 and serum response factor (SRF) showed reduced levels of DNA binding activities in old fibroblasts compared to young cells. A probe for the TGF beta-inhibitory element (TIE) gave equivalent levels of complexes with nuclear extracts from both types of cells, though of different mobilities. We conclude that the effects of TGF beta 1 on MMP and TIMP gene expression involve different cellular intermediaries, and suggest that altered composition or modification of TIE binding factors in aging cells may underlie the failure of TGF beta 1-mediated transcription repression. This mechanism may contribute to elevated constitutive expression of MMPs in old cells and to the connective tissue deterioration that accompanies the aging process.

Cells, Cultured↗
PubMedDate not supplied

Amplification of inter-Alu extrachromosomal DNA during cellular ageing: retraction and explanation.

We reported previously the age-dependent appearance of extrachromosomal circular DNA bands hybridizing to a human DNA fragment ('inter-Alu'), isolated from a genomic cluster of AluI repeats. Such bands appeared or increased at late passage in four out of six human fibroblast strains (six out of nine cell expansions); moreover, all DNAs (9/9) obtained from peripheral lymphocytes of aged donors, but none (0/8) from young donors, revealed a non-genomic inter-Alu band at congruent to 4.8 kilobases (kb). Subsequent data extended these numbers to 16/24 aged donors compared with 0/18 young donors. These results were interpreted as evidence of age-dependent DNA rearrangement in normal human cells. We now report that the 'extra' bands were of microbial origin, although clearly occurring in an age-dependent manner.

Aged↗
PubMedDate not supplied

Transcription factor activity during cellular aging of human diploid fibroblasts.

Human diploid fibroblasts display a limited proliferative life span in vitro, which is directly correlated to the age of the donor from which the cells were explanted. In an effort to identify molecular events that may underlie the loss of proliferative potential in aging fibroblasts, we have determined, at the protein level, the abundance of several cell-cycle-regulated proteins and the activity of the two major members of the activator protein-1 (AP-1) DNA binding complex. We find that cyclin A and p34cdc2 expression is decreased by two- to four-fold in old fibroblasts, but that Fos expression and binding activity are reduced by as much as 95% in old, as opposed to young cells, despite equivalent amounts of p105Rb and Jun proteins being expressed. We have further determined that the composition of the protein complex which binds a consensus (-TGACTCA-) AP-1 site changes dramatically during in vitro aging. Since we have shown previously that AP-1 activity is required for progression through the cell cycle, we propose that the quantitative and qualitative changes seen in AP-1 may play a direct role in the gradual loss of proliferative ability seen as cells approach senescence.

Base Sequence↗
PubMedDate not supplied

Regulation of gene expression and transcription factor binding activity during cellular aging.

Human diploid fibroblasts (HDFs) undergo a limited number of population doublings in vitro and are widely used as a model of cellular aging. Despite growing evidence that cellular aging occurs as a result of altered gene expression, little is known about the activity of transcription factors that regulate gene expression in aging cells. Here we survey the relevant literature regarding altered gene expression and the role of transcription factors during cellular aging, focusing upon the serum response factor (SRF). SRF is hyperphosphorylated in senescent HDFs and fails to bind to the serum-response element in the c-fos promoter. Differential phosphorylation during replicative aging may contribute, at least in part, to the altered activity of SRF and possibly other transcription factors and to subsequent changes in the expression of serum-regulated genes in senescent HDFs.

Cell Physiological Phenomena↗